WO1983003054A1 - A proces for producing an insulin preparation - Google Patents
A proces for producing an insulin preparation Download PDFInfo
- Publication number
- WO1983003054A1 WO1983003054A1 PCT/DK1983/000024 DK8300024W WO8303054A1 WO 1983003054 A1 WO1983003054 A1 WO 1983003054A1 DK 8300024 W DK8300024 W DK 8300024W WO 8303054 A1 WO8303054 A1 WO 8303054A1
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- WO
- WIPO (PCT)
- Prior art keywords
- insulin
- zinc
- process according
- preparation
- weight
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
Definitions
- the present invention relates to a process for preparing a stable, quick-acting insulin preparation of the type defined in the introductory portion of claim 1.
- the present insulin preparation is suitable for use in insulin delivery devices.
- the previously known insulin preparations are intended for storage at rest at 4oC.
- the insulin preparation is stored in the reservoir of insulin devices for an extended period of time at temperatures between 30 and 37oC, and is moreover subjected to a good deal of motion during this period.
- the previously known dissolved insulin preparations are usually produced from zinc-crystallized insulin and are admixed with the necessary and known medium components, such as preservative, isotonic and buffer to maintain the pH, and the zinc content may optionally be adjusted with a zinc salt.
- the art also comprises insulin preparations which are not produced on the basis of zinc-crystallized insulin.
- the Danish Patent Specifications 127 165, 143 024 and 143 106 teach processes, for preparing and purifying alkali metal and ammonium insulin, i.e. insulin crystallized with lithium, sodium, potassium or ammonium instead of zinc, while the Danish Patent Specification 140 801 concerns a process for preparing insulin preparations with protracted action, in which the crystallization step is omitted because immediately after the purification of crude insulin the purified insulin is passed into the preparation medium comprising an amino group containing a base, and finally the pH and optionally the zinc content are adjusted.
- These methods have been developed to provide better yields and preparations of lower antigenicity, respectively.
- the insulin starting material used for making the preparation must be essentially zinc-free, preferably not zinc crystallized. Useful insulins are stated in claim 2 and the preferred insulin in claim 3.
- aqueous medium does not contain di- or polyvalent ions which would impair the stability, but only monovalent ions.
- the preparation medium is to be admixed with a zinc salt so that the zinc content of the finished preparation constitutes 0.5 to 1.0%, based on the weight of insulin, preferably 0.7 to 0.9%, such as 0.76 to 0.84, the optimum content being around 0.8%.
- the pH of the medium is to be in the range of 6.9 to 8.9, preferably 6.9 to 7.8.
- the optimum range is 7.2 to 7.8, such as 7.4.
- a non-dissociable isotonic such as glycerol, or a nonreducible sugar type may be added.
- a suitable sugar type is mannitol.
- the preservative used may be a phenol or an alkyl- substituted phenol, preferably m-cresol.
- a preparation thus produced usually requires no addition of a buffer, in particular in case of insulin concentrations of 100 to 1500 IU/ml, because the insulin molecule itself exerts an adequate buffer effect.
- common buffers such as sodium acetate, or more special buffers of the amine or amide type, such as tyrosine amide.
- the present process is useful in connection with insulin of different purity, such as repeatedly recrystallized products or the so-called highly purified types which are almost completely freed of antigenic impurities.
- Sodium-crystallized insulin corresponding to 100,000 IU was dissolved in 800 ml of sterile, distilled water. Then 16 g of glycerol and 5 g of phenol were added with stirring. This was followed by addition of a solution of ZnCl 2 containing an amount of zinc corresponding to 0.8% of the insulin amount, determined by Kjeldahl's method, and the solution was topped with sterile, distilled water to 990 ml. Finally, the pH of the solution was adjusted to 7.4 with 0.1 N NaOH and its volume was adjusted to 1000 ml with sterile, distilled water, followed by sterile filtration of the solution.
- Sodium crystallized insulin corresponding to 100,000 IU was dissolved in 200 ml of sterile distilled water, and pH was adjusted to 8.1 with 0.1 N NaOH or 0.1 N HCl. 16 g of glycerol and 3.3 g of m-cresol were dissolved in about 700 ml of sterile distilled water. This was followed by addition of a solution of ZnCl 2 containing an amount of zinc corresponding to 0.8% of the insulin amount, determined by Kjeldahl's method. Then the pH of the medium was adjusted to 6.9 with 0.1 N NaOH and its volume to 790 ml with sterile distilled water. The medium was carefully added to the 200 ml of insulin solution with stirring. Finally, the pH of the solution was adjusted to 7.4 with 0.1 N NaOH, optionally 0.1 N HCl, and its volume to 1000 ml with sterile distilled water, and the solution was sterile filtrated.
- Freeze-dried, essentially zinc-free insulin corresponding to 100,000 IU was dissolved in 800 ml of sterile, distilled water. The pH was adjusted to 7.8 with 0.1 N NaOH. The solution, was admixed, with stirring, with 1 g of NaCl and 3.0 g of m-cresol. This was followed by addition of a solution of ZnCl 2 containing an amount of zinc corresponding to 0.8% of the insulin amount, determined by Kjeldahl's method, and the solution was topped with sterile, distilled water to 990 ml. Finally, the pH of the solution was adjusted to 7.8 with 0.1 N NaOH and its volume was adjusted to 1000 ml with sterile, distilled water, followed by sterile filtration of the solution. EXAMPLE 4
- a column of a diameter of 2.5 cm was packed at room temperature with a 75 cm high layer of Sephadex ® G25 medium swollen in distilled water.
- an insulin solution resulting from ion exchange in a known manner on DEAE cellulose in a 7 molar urea solution there were applied 40 ml containing insulin corresponding to 20,000 IU after concentration and adjustment of the pH of the solution to 8.2. This was followed by elution with distilled water at a rate of 108 ml/h, and the eluate was divided into fractions. The extinction at 280 run was measured, and the fractions containing insulin were collected, followed by determination of the insulin content.
- Part of the resulting insulin solution containing insulin corresponding to 10,000 IU was diluted with sterile, distilled water to 80 ml.
- the solution was admixed, with stirring, with 1.6 g of glycerol, 0.2 g of NaCl and 0.33 g of m-cresol.
- a solution of ZnCl 2 containing an amount of zinc corresponding to 0.8% of the insulin amount, determined by Kjeldahl's method, and the solution was topped with sterile, distilled water to 95 ml.
- the pH of the solution was adjusted, to 7.4 with 0.1 N NaOH, and its volume was adjusted -to 100 ml with sterile, distilled water, followed by sterile filtration of the solution.
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- Gastroenterology & Hepatology (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
Une préparation d'insuline stable et d'action rapide est produite en dissolvant de l'insuline exempte de zinc dans un milieu aqueux contenant des ions monovalents, tels que des ions de sodium, mais pratiquement pas d'ions bivalents ou polyvalents, en réglant le pH entre 6,9 et 8,0, de préférence entre 7,2 et 7,8, et en ajoutant un composé de zinc correspondant à une quantité de 0,5 à 1,0 % de zinc, de préférence de 0,7 à 0,9 % de zinc, en fonction du poids de l'insuline. La préparation est très stable contre l'aggrégation entre 25 et 37oC, et convient donc particulièrement à l'utilisation dans des dispositifs portatifs ou implantables d'administration d'insuline.A stable, fast-acting insulin preparation is produced by dissolving zinc-free insulin in an aqueous medium containing monovalent ions, such as sodium ions, but practically no bivalent or polyvalent ions, by regulating the pH between 6.9 and 8.0, preferably between 7.2 and 7.8, and by adding a zinc compound corresponding to an amount of 0.5 to 1.0% of zinc, preferably 0, 7 to 0.9% zinc, depending on the weight of the insulin. The preparation is very stable against aggregation between 25 and 37oC, and is therefore particularly suitable for use in portable or implantable insulin delivery devices.
Description
A process for producing an insulin preparation
The present invention relates to a process for preparing a stable, quick-acting insulin preparation of the type defined in the introductory portion of claim 1. The present insulin preparation is suitable for use in insulin delivery devices.
It is generally held that most of the complications that may arise in connection with an insulin-dependent diabetes can be ascribed to inadequate control of the glucose content in the blood (Tehobroutsky, Diabetologia, 15, 143-152 (1978)). In the conventional insulin therapy, insulin is administered to the diabetic by way of one to three injections per day, resulting in a fluctuating insulin and glucose content in the blood. In contrast, the non-diabetic constantly receives insulin from his pancreas, secreted in the blood stream and in an amount adapted to his needs.
In recent years efforts have therefore been made to develop insulin delivery devices which can remedy the above-mentioned problem. If, however, such devices are applied internally or externally to a human, the insulin preparation experiences far inferior storage conditions in terms of temperature and motion when stored in the reservoir of the device than the injectable preparations.
The previously known insulin preparations are intended for storage at rest at 4ºC. In contrast, the insulin preparation is stored in the reservoir of insulin devices for an extended period of time at temperatures between 30 and 37ºC, and is moreover subjected to a good deal of motion during this period.
Thus, it is understandable that it has turned out that
in the use of the conventional dissolved insulin preparations in delivery devices, the supply tubes, valves and filters of the system are often gradually blocked by precipitated insulin aggregates, and that the desired very precise dosing of the insulin into the blood stream is prevented by this. These problems of aggregation have been discussed in great detail by W.D. Lougheed et al., Diabetologia 19, 1-9 (1980), reporting that the varying tendency to aggregation may be attributable to temperature, ion concentration and type, pH value, presence of carbon dioxide and other gases, as well as other factors.
It. has been found that the quality of the insulin reaching the blood stream after an extended stay in a delivery device with associated reservoir is significantly inferior to the quality after storage and use under the common conditions. This, too, is understandable because of the aggregation and/or formation of denatured insulin which takes place during the storage in the reservoir of the delivery device.
In the past it was attempted to solve these problems by adding to the known insulin solutions special substances - e.g. surfactants of a chain-like basic structure whose links contain alternating slightly hydrophobic and slightly hydrophilic areas, cf. the Danish Application 1851/80 - with the sole task of stabilizing the solution. Addition of such surfactants is reported to provide preparations which has such stabilizing properties as make them satisfy the technological requirements made of the use of insulin delivery devices. However, in medical circles among others there is a wish for avoiding the addition of such new substances to the known insulin preparations, which have been tested for decades, because of lack of experience with respect to the effect
of such substances on the human organism. Accordingly, there is a need for insulin preparations sufficiently stable for practical purposes without addition of special substances, even if this might result in a stability which is not of quite the same order as can be obtained by using the special additives.
The previously known dissolved insulin preparations are usually produced from zinc-crystallized insulin and are admixed with the necessary and known medium components, such as preservative, isotonic and buffer to maintain the pH, and the zinc content may optionally be adjusted with a zinc salt.
However, the art also comprises insulin preparations which are not produced on the basis of zinc-crystallized insulin. Thus, the Danish Patent Specifications 127 165, 143 024 and 143 106 teach processes, for preparing and purifying alkali metal and ammonium insulin, i.e. insulin crystallized with lithium, sodium, potassium or ammonium instead of zinc, while the Danish Patent Specification 140 801 concerns a process for preparing insulin preparations with protracted action, in which the crystallization step is omitted because immediately after the purification of crude insulin the purified insulin is passed into the preparation medium comprising an amino group containing a base, and finally the pH and optionally the zinc content are adjusted. These methods have been developed to provide better yields and preparations of lower antigenicity, respectively.
It has now surprisingly been found that an extremely stable insulin preparation, which retains its stability during shaking tests at 30 ºCfor several weeks, can be obtained by proceeding as stated in the characterizing portion of claim 1.
The invention is thus based on a combination of critical parameters:
The insulin starting material used for making the preparation must be essentially zinc-free, preferably not zinc crystallized. Useful insulins are stated in claim 2 and the preferred insulin in claim 3.
It is important that the aqueous medium does not contain di- or polyvalent ions which would impair the stability, but only monovalent ions.
The preparation medium is to be admixed with a zinc salt so that the zinc content of the finished preparation constitutes 0.5 to 1.0%, based on the weight of insulin, preferably 0.7 to 0.9%, such as 0.76 to 0.84, the optimum content being around 0.8%.
The pH of the medium is to be in the range of 6.9 to 8.9, preferably 6.9 to 7.8. The optimum range is 7.2 to 7.8, such as 7.4.
A non-dissociable isotonic, such as glycerol, or a nonreducible sugar type may be added. A specific example of a suitable sugar type is mannitol.
The preservative used may be a phenol or an alkyl- substituted phenol, preferably m-cresol.
It has been found that a preparation thus produced usually requires no addition of a buffer, in particular in case of insulin concentrations of 100 to 1500 IU/ml, because the insulin molecule itself exerts an adequate buffer effect.
However, nothing prevents the addition of common buffers, such as sodium acetate, or more special buffers of the amine or amide type, such as tyrosine amide.
Without being tied down to any specific theory, it is believed that certain problems of denaturation and aggregation observed in connection with zinc crystallization can be avoided by using an essentially zinc-free, preferably not zinc crystallized insulin as the starting material.
The subsequent addition of relatively large amounts of z.inc to the medium presumably causes formation of dissolved insulin hexamer in reversible equilibrium with monomeric and dimeric insulin.
The present process is useful in connection with insulin of different purity, such as repeatedly recrystallized products or the so-called highly purified types which are almost completely freed of antigenic impurities.
The process of the invention will be illustrated in greater detail by the following examples.
EXAMPLE 1
Sodium-crystallized insulin corresponding to 100,000 IU was dissolved in 800 ml of sterile, distilled water. Then 16 g of glycerol and 5 g of phenol were added with stirring. This was followed by addition of a solution of ZnCl2 containing an amount of zinc corresponding to 0.8% of the insulin amount, determined by Kjeldahl's method, and the solution was topped with sterile, distilled water to 990 ml. Finally, the pH of the solution was adjusted to 7.4 with 0.1 N NaOH and its volume was adjusted to 1000 ml with sterile, distilled water,
followed by sterile filtration of the solution.
EXAMPLE 2
Sodium crystallized insulin corresponding to 100,000 IU was dissolved in 200 ml of sterile distilled water, and pH was adjusted to 8.1 with 0.1 N NaOH or 0.1 N HCl. 16 g of glycerol and 3.3 g of m-cresol were dissolved in about 700 ml of sterile distilled water. This was followed by addition of a solution of ZnCl2 containing an amount of zinc corresponding to 0.8% of the insulin amount, determined by Kjeldahl's method. Then the pH of the medium was adjusted to 6.9 with 0.1 N NaOH and its volume to 790 ml with sterile distilled water. The medium was carefully added to the 200 ml of insulin solution with stirring. Finally, the pH of the solution was adjusted to 7.4 with 0.1 N NaOH, optionally 0.1 N HCl, and its volume to 1000 ml with sterile distilled water, and the solution was sterile filtrated.
EXAMPLE 3
Freeze-dried, essentially zinc-free insulin corresponding to 100,000 IU was dissolved in 800 ml of sterile, distilled water. The pH was adjusted to 7.8 with 0.1 N NaOH. The solution, was admixed, with stirring, with 1 g of NaCl and 3.0 g of m-cresol. This was followed by addition of a solution of ZnCl2 containing an amount of zinc corresponding to 0.8% of the insulin amount, determined by Kjeldahl's method, and the solution was topped with sterile, distilled water to 990 ml. Finally, the pH of the solution was adjusted to 7.8 with 0.1 N NaOH and its volume was adjusted to 1000 ml with sterile, distilled water, followed by sterile filtration of the solution.
EXAMPLE 4
A column of a diameter of 2.5 cm was packed at room temperature with a 75 cm high layer of Sephadex ® G25 medium swollen in distilled water. Of an insulin solution resulting from ion exchange in a known manner on DEAE cellulose in a 7 molar urea solution there were applied 40 ml containing insulin corresponding to 20,000 IU after concentration and adjustment of the pH of the solution to 8.2. This was followed by elution with distilled water at a rate of 108 ml/h, and the eluate was divided into fractions. The extinction at 280 run was measured, and the fractions containing insulin were collected, followed by determination of the insulin content. Part of the resulting insulin solution containing insulin corresponding to 10,000 IU was diluted with sterile, distilled water to 80 ml. The solution was admixed, with stirring, with 1.6 g of glycerol, 0.2 g of NaCl and 0.33 g of m-cresol. Then there was added a solution of ZnCl2 containing an amount of zinc corresponding to 0.8% of the insulin amount, determined by Kjeldahl's method, and the solution was topped with sterile, distilled water to 95 ml. Finally, the pH of the solution was adjusted, to 7.4 with 0.1 N NaOH, and its volume was adjusted -to 100 ml with sterile, distilled water, followed by sterile filtration of the solution.
The preparations described in the examples were tested for stability by shaking tests at 30 ºCwith 70 os/min in horizontal 3/4 filled vials, which is tantamount to extreme conditions compared to the storage in the reservoir in a delivery device.
The preparations produced in examples 1, 3 and 4 were found to be stable for more than 360 hours, while example
2 provides for stability of about 1500 hours.
Common commercial quick-acting neutral insulin solutions were found to have inferior stability in corresponding tests. Thus, the stability of an insulin preparation produced as described in example 1 of the US Patent Specification 3 091 573 lasts for about 24 hours. The stability of an insulin preparation produced according to example 1 of the Danish Patent Specification 95007 was determined to be about 97 hours.
Claims
1. A process for producing a stable, quick-acting insulin preparation which is a clear solution at neutral pH and suitable for use in insulin delivery devices in concentrations of up to 1500 IU/ml, comprising dissolving insulin in an aqueous carrier and adding common medium components, such as isotonics and preservatives, c h a r a c t e r i z e d by dissolving essentially zinc-free insulin in the aqueous medium which contains monovalent ions, but substantially no di- or polyvalent ions, adjusting the pH to a desired value, in the range of 6.9 to 8.0, if desired using a buffer active in said pH range, adding a zinc compound in an amount corresponding to 0.5 to 1.0% zinc, based on the weight of insulin, and optionally adjusting the insulin content to a desired value.
2. A process according to claim 1, c h a r a c t e r i z e d by selecting the essentially zinc-free insulin starting material from among alkali metal crystallized or ammonium crystallized insulin, isoelectrically precipitated insulin, chromatographically purified insulin solutions or freeze-dried insulin.
3. A process according to claim 2, c h a r a c t e r i z e d in that the alkali metal crystallized insulin is insulin crystallized by addition of 10% w/v sodium chloride after adjustment of pH to the range of 8.2 to 8.5 with sodium hydroxide.
4. A process according to claims 1-3, c h a r a c t e ri z e d by adjusting the pH of the medium to a range of 6.9 to 7.8, preferably 7.2 to 7.8, such as 7.4.
5. A process according to claims 1-4, c h a r a c t e ri z e d by adding a zinc compound in an amount corresponding to 0.7 to 0.9% zinc, based on the weight of insulin.
6. A process according to claim 5, c h a r a c t e r i z e d by adding a zinc compound in an amount corresponding to 0.76 to 0.84% zinc, based on the weight of insulin.
7. A process according to claims 1- 6, c h a r a ct e r i z e d in that an aqueous solution of essentially zinc-free insulin having no di- or polyvalent ions is adjusted to a pH of about 8 and is admixed with an aqueous medium containing the desired medium components as well as a zinc compound in an amount corresponding to 0.76 - 0.84% zinc, based on the weight of insulin, and then the pH of the preparation is adjusted to 7.2 - 7.7.
8. A process according to claims 1-6 for producing a stable, quick-acting insulin preparation which at a pH of 6.9 - 8.0 is a clear solution in an aqueous medium and is suitable for use in insulin delivery devices, said insulin preparation containing insulin in concentrations of up to 1500 IU /ml and 0.5 - 1.0 % zinc, based on the weight of insulin, and desired medium components, such as isotonics, pH-buffers and preservatives, c h a r a c t e r i z e d in that an aqueous solution of essentially zinc-free insulin essentially without any di- or polyvalent ions is adjusted to the desired pH and admixed with the medium components as well as a zinc compound to provide the desired zinc concentration.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU13399/83A AU1339983A (en) | 1982-03-03 | 1983-03-02 | A process for producing an insulin preparation |
| DK402983A DK402983A (en) | 1982-03-03 | 1983-09-05 | PROCEDURE FOR PREPARING AN INSULIN PREPARATION |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK91882 | 1982-03-03 | ||
| DK918/82820303 | 1982-03-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1983003054A1 true WO1983003054A1 (en) | 1983-09-15 |
Family
ID=8099004
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/DK1983/000024 Ceased WO1983003054A1 (en) | 1982-03-03 | 1983-03-02 | A proces for producing an insulin preparation |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0102976A1 (en) |
| ES (1) | ES8403723A1 (en) |
| WO (1) | WO1983003054A1 (en) |
Cited By (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2521009A1 (en) * | 1982-02-05 | 1983-08-12 | Novo Industri As | STABILIZED SOLUTIONS OF INSULIN AND PROCESS FOR THE PREPARATION THEREOF |
| EP0709395A3 (en) * | 1994-10-31 | 1996-09-04 | Lilly Co Eli | Preparation of stable insulin analog crystals |
| AU753673B2 (en) * | 1997-08-04 | 2002-10-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Aqueous aerosol preparations containing biologically active macromolecules and method for producing the corresponding aerosols |
| RU2202365C2 (en) * | 2001-07-20 | 2003-04-20 | Институт биоорганической химии им. М.М.Шемякина и Ю.А.Овчинникова РАН | Method for preparing quick action insulin solution for making injections |
| RU2251426C1 (en) * | 2003-09-18 | 2005-05-10 | Цыганков Владимир Владимирович | Method for obtaining insulin out of natural source and insulin |
| RU2252752C2 (en) * | 2002-05-15 | 2005-05-27 | Ооо Мако | Human insulin drug of short action |
| RU2252782C2 (en) * | 2001-12-29 | 2005-05-27 | Алексей Павлович Лазарев | Method for production of insulin drug of durable action |
| RU2261107C2 (en) * | 2001-12-29 | 2005-09-27 | Алексей Павлович Лазарев | Method for preparing ready medicinal formulation of insulin with short effect |
| RU2261108C2 (en) * | 2001-12-29 | 2005-09-27 | Алексей Павлович Лазарев | Method for preparing human insulin combined preparation |
| RU2281756C2 (en) * | 2004-11-25 | 2006-08-20 | Институт биоорганичексой химии им. академиков М.М. Шемякина и. Ю.А. Овчинникова Российской Академии Наук | Method for preparing pharmaceutical composition suspension based on substance of human genetic engineering (recombinant) insulin |
| AU2002300833B2 (en) * | 1997-08-04 | 2007-05-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Aqueous aerosol preparations containing biologically active macromolecules and method for producing the corresponding aerosols |
| US9545487B2 (en) | 2012-04-13 | 2017-01-17 | Boehringer Ingelheim International Gmbh | Dispenser with encoding means |
| US9682202B2 (en) | 2009-05-18 | 2017-06-20 | Boehringer Ingelheim International Gmbh | Adapter, inhalation device, and atomizer |
| US9724482B2 (en) | 2009-11-25 | 2017-08-08 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US9744313B2 (en) | 2013-08-09 | 2017-08-29 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US9757750B2 (en) | 2011-04-01 | 2017-09-12 | Boehringer Ingelheim International Gmbh | Medicinal device with container |
| US9827384B2 (en) | 2011-05-23 | 2017-11-28 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US9943654B2 (en) | 2010-06-24 | 2018-04-17 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US10004857B2 (en) | 2013-08-09 | 2018-06-26 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US10011906B2 (en) | 2009-03-31 | 2018-07-03 | Beohringer Ingelheim International Gmbh | Method for coating a surface of a component |
| US10016568B2 (en) | 2009-11-25 | 2018-07-10 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US10099022B2 (en) | 2014-05-07 | 2018-10-16 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US10124129B2 (en) | 2008-01-02 | 2018-11-13 | Boehringer Ingelheim International Gmbh | Dispensing device, storage device and method for dispensing a formulation |
| US10124125B2 (en) | 2009-11-25 | 2018-11-13 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US10195374B2 (en) | 2014-05-07 | 2019-02-05 | Boehringer Ingelheim International Gmbh | Container, nebulizer and use |
| US10722666B2 (en) | 2014-05-07 | 2020-07-28 | Boehringer Ingelheim International Gmbh | Nebulizer with axially movable and lockable container and indicator |
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| US3091573A (en) * | 1958-05-12 | 1963-05-28 | Novo Terapeutisk Labor As | Quick acting insulin preparation |
| DE1212679B (en) * | 1957-08-03 | 1966-03-17 | Novo Terapeutisk Labor As | Process for the preparation of insulin solutions |
| US3584121A (en) * | 1967-03-01 | 1971-06-08 | Nordisk Insulinlab | Quick-acting,stable,neutral solution of bovine insulin and process for the production thereof |
| US3657425A (en) * | 1969-03-12 | 1972-04-18 | Burroughs Wellcome Co | Beef insulin preparations |
| US3719655A (en) * | 1969-12-05 | 1973-03-06 | Lilly Co Eli | Process for the crystallization of the ammonium and alkali metal salts in insulin |
| US3876623A (en) * | 1973-05-09 | 1975-04-08 | Lilly Co Eli | Process for purifying insulin |
| US3878186A (en) * | 1973-05-09 | 1975-04-15 | Lilly Co Eli | Process for purifying insulin |
| DE3107168A1 (en) * | 1980-02-29 | 1981-12-24 | Hospital For Sick Children | NON-AGREED SOLUTIONS OF POLYPEPTIDES |
-
1983
- 1983-03-02 ES ES520249A patent/ES8403723A1/en not_active Expired
- 1983-03-02 EP EP19830900834 patent/EP0102976A1/en not_active Withdrawn
- 1983-03-02 WO PCT/DK1983/000024 patent/WO1983003054A1/en not_active Ceased
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|---|---|---|---|---|
| DE1212679B (en) * | 1957-08-03 | 1966-03-17 | Novo Terapeutisk Labor As | Process for the preparation of insulin solutions |
| US3091573A (en) * | 1958-05-12 | 1963-05-28 | Novo Terapeutisk Labor As | Quick acting insulin preparation |
| US3584121A (en) * | 1967-03-01 | 1971-06-08 | Nordisk Insulinlab | Quick-acting,stable,neutral solution of bovine insulin and process for the production thereof |
| US3657425A (en) * | 1969-03-12 | 1972-04-18 | Burroughs Wellcome Co | Beef insulin preparations |
| US3719655A (en) * | 1969-12-05 | 1973-03-06 | Lilly Co Eli | Process for the crystallization of the ammonium and alkali metal salts in insulin |
| US3876623A (en) * | 1973-05-09 | 1975-04-08 | Lilly Co Eli | Process for purifying insulin |
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| DE3107168A1 (en) * | 1980-02-29 | 1981-12-24 | Hospital For Sick Children | NON-AGREED SOLUTIONS OF POLYPEPTIDES |
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| Diabetologia, Vol. 19, no. 1, issued 1980 July (Springer-Verlag, Berlin), W D LOUGHEED ET AL, "Insulin aggregation in artificial delivery systems", see pages 1-9, especially page 3, the first passage. * |
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Also Published As
| Publication number | Publication date |
|---|---|
| ES520249A0 (en) | 1984-04-16 |
| ES8403723A1 (en) | 1984-04-16 |
| EP0102976A1 (en) | 1984-03-21 |
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